Taxane delivery system

a delivery system and taxane technology, applied in the field of drug delivery, to achieve the effect of facilitating pharmacokinetic control

Active Publication Date: 2013-07-16
CELATOR PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The present invention employs prodrugs of a taxane and micellar or nanoparticle delivery vehicles to facilitate pharmacokinetic control. By making the taxane more hydrophobic and consequently more compatible with lipid based delivery systems, the pharmacokinetics of the taxane compositions can be controlled. It is also possible to adjust the properties of formulations containing additional antineoplastic agents such that their effective release rates in vivo are matched to that of the taxane. Micelles or lipophilic nanoparticle carriers can be used to suspend these prodrugs and other agents in an aqueous environment.
[0009]As shown below, long circulating diglycolate prodrug nanoparticles provide significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose; these types of formulations are therefore advantageous per se.

Problems solved by technology

There are many reports in the literature describing attempts to improve the formulation of paclitaxel using micelles, liposomes or emulsions.1, 15, 16, 17 In almost all cases, however, it is clear from the reported pharmacokinetic data that while these carriers formulate paclitaxel, they do not act as true delivery vehicles in vivo since the drug rapidly partitions out of the carrier with half lives on the order of minutes.
Most of these reports claim improved efficacy over paclitaxel in in vivo models, however, in most cases they either provide no information on plasma drug elimination or present data focusing on the terminal drug elimination phase rather than the early distribution phase.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Prodrug

[0035]A range of commonly available lipid alcohols were used as the anchor component (Scheme 1), including α-tocopherol (1 and 3), oleyl alcohol (2 and 4), octadecanol (5), cosanol (6), docosanol (7), cholesterol (8) and 1,2-dimyristoyl-sn-glycerol (9). The lipids were conjugated to the cross-linker by treatment with the corresponding cyclic anhydride, followed by condensation of the anchor-linker product with paclitaxel using diisopropylcarbodiimide (DIPC) in the presence of N,N-4-dimethylaminopyridine (DMAP). Succinic acid (1-2) and diglycolic acid (3-9) were used as the cross-linkers. The 3-oxa moiety of the latter was intended to increase the susceptibility of the 2′-acyl group of the cross-linker to hydrolysis relative to the succinate analogues.

[0036]

[0037]

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[0038]

[0039]The 2′-acyl paclitaxel derivatives were prepared selectively by exploiting the difference in reaction rates between the paclitaxel 2′- and 7-hydroxyl groups. Under the reaction cond...

example 2

Nanoparticle Formulation

[0052]The prodrug, co-lipid and stabilizer polymers (typically on a 1:1:2 w / w basis) were dissolved in ethanol / THF (4:1) at a concentration of 40 mg / ml. The solvent was rapidly diluted with water using a four port CVIJ mixer13, 14 with flow rates set at Dec. 12, 1953 / 53 ml / min (solvent / water / water / water). Flow rates were controlled using Harvard Apparatus PHD2000 syringe pumps. The resultant solution was then dialyzed against water to remove residual solvent. The final drug concentration was typically about 0.7 mg / ml. When higher concentrations were required the dialyzed solution was diluted with equi-volumes of 600 mM sucrose and then concentrated using a 100 kD, 0.5 mm lumen, 60 cm path length MidGee hoop cartridge (GE Healthcare Life Sciences, Piscataway, N.J.) with a peristaltic pump. Particle size was determined using a Malvern Zetasizer Nano-ZS particle sizer and reported as volume weighted data.

[0053]Formulations were composed of a prodrug, a co-lipid ...

example 3

In Vitro Activity

[0062]The MCF-7 human tumor cell line was purchased from American Type culture Collection (Manassas, Va.). The A2780 human tumor cell line was purchased from the European Collection of Cell culture (UK).

[0063]Cells were exposed in triplicates to a serial dilution of prodrug / POPC / 2.5kPS3k (1:1:2) nanoparticle formulations for 72 hours at 16 concentrations. Viable cells were quantified using standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) detection at 570 nm after DMSO addition. Survival rate after treatment is expressed as a mean percentage relative to untreated control wells.

[0064]Evaluation of prodrug cytotoxicity was carried out using A2780 and MCF-7 human tumor cells treated with prodrug / POPC / 2.5kPS3k (1:1:2) formulations prepared in distilled water (Table 2). Control formulations containing no prodrug confirmed that other nanoparticle components did not contribute to the growth inhibition of the cells. In addition, 1 was evaluated usi...

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Abstract

Nanoparticulate formulations for delivery of taxane conjugate prodrug formed from a taxane coupled to a hydrophobic moiety through a glycolate linker are described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is the national phase of PCT application PCT / US2008 / 085030 having an international filing date of 26 Nov. 2008, which claims benefit of U.S. provisional application No. 60 / 990,907 filed 28 Nov. 2007. The contents of the above patent applications are incorporated by reference herein in their entirety.RELATED APPLICATION[0002]This application claims benefit of U.S. application Ser. No. 60 / 990,907 filed 28 Nov. 2007 which is incorporated herein by reference in its entirety.TECHNICAL FIELD[0003]The invention is in the field of drug delivery, specifically in the area of successful delivery of taxanes with controlled pharmacokinetics.BACKGROUND ART[0004]Paclitaxel is a widely used chemotherapeutic agent for treating a range of carcinomas. The clinical material is formulated in Cremophor® EL / ethanol, and is diluted with buffer prior to administration. There are many reports in the literature describing attempts to improve the fo...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/58A61K31/27A61K31/335A61K47/00
CPCA61K9/1075A61K9/5123A61K47/48046A61K31/337C07D305/14A61K9/5146A61K47/543A61P35/00A61P43/00
Inventor ANSELL, STEVEN M.JOHNSTONE, SHARONTARDI, PAULMAYER, LAWRENCE
Owner CELATOR PHARMA INC
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